Project Summary Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and is characterized by irreversible expiratory airflow limitation in response to noxious stimuli (e.g., cigarette smoke). Emphysema, with destructive enlargement of the airspaces, is an important phenotype of COPD that accounts for high mortality rates. Accumulating evidence suggest a causative role of DNA damage and lung epithelial cell apoptosis in emphysema pathogenesis. However, the molecular basis for cigarette smoke-induced DNA damage and apoptosis remains to be elucidated. Our genomic and functional studies identified TACC2 that encodes a centrosome-interacting protein as a COPD candidate gene. Our novel preliminary data demonstrate that smokers with COPD exhibit a marked decrease in TACC2 relative to smokers without COPD. We also observed that Tacc2-/- compared to Tacc2+/+ mice when exposed to cigarette smoke exhibit emphysematous changes accompanied by DNA damage. TACC2 knockdown impairs homologous recombination, and augments cigarette smoke-induced DNA damage and cytotoxicity in immortalized human bronchial epithelial cells (HBEC). Cigarette smoke significantly reduces TACC2 protein via the ubiquitin-proteasome pathway. Indeed, a proapoptotic, ubiquitin E3 ligase subunit, termed F box L7 (FBXL7), targets TACC2 for its degradation in cells. Furthermore, TACC2 is found to associate with ataxia telangiectasia mutated (ATM), a key DNA damage-sensing kinase, and the association is stimulated by cigarette smoke. These preliminary data led us to an overarching hypothesis that cigarette smoke induces the ATM-mediated DNA damage response through a TACC2-dependent mechanism that is impaired in COPD, leading to lung epithelial cell apoptosis and the formation of emphysema. In Aim 1, we will determine whether TACC2 acts through ATM to control cigarette smoke-induced DNA damage response and cytotoxicity in lung epithelial cells. In Aim 2, we will determine whether ATM-dependent phosphorylation of TACC2 promotes its FBXL7-mediated degradation in cigarette smoke-exposed lung epithelial cells. In Aim 3, we will determine whether increased TACC2 stability protects against cigarette smoke-induced DNA damage response, lung epithelial cell apoptosis, and emphysema. Completion of the proposed studies will elucidate the mechanisms of smoking-induced DNA damage accumulation in COPD lungs and will potentially lead to development of a novel therapeutic approach for this debilitating disease.